Regioselective synthesis of 1,3,4,5-Tetrasubstituted Pyrazoles from α-Alkenyl-α,β-Enones derived from Morita-Baylis-Hillman adducts

Article abstract of DOI:10.5012/bkcs.2013.34.10.2915

Convenient synthetic method for 4-arylethylpyrazoles and 4-styrylpyrazoles was developed using α-alkenyl- α,β-enones readily accessed from the Morita-Baylis-Hillman reaction. For the synthesis of 4-arylethylpyrazole, the reactions with arylhydrazines need

Full text of DOI:10.5012/bkcs.2013.34.10.2915

Regioselective Synthesis of 1,3,4,5-Tetrasubstituted Pyrazoles
Bull. Korean Chem. Soc. 2013, Vol. 34, No. 10 2915
http://dx.doi.org/10.5012/bkcs.2013.34.10.2915
Regioselective Synthesis of 1,3,4,5-Tetrasubstituted Pyrazoles from
α-Alkenyl-α,β-Enones Derived from Morita-Baylis-Hillman Adducts
*
Sung Hwan Kim, Jin Woo Lim, Jin Yu, and Jae Nyoung Kim
Department of Chemistry and Institute of Basic Science, Chonnam National University, Gwangju 500-757, Korea
*
E-mail: kimjn@chonnam.ac.kr
Received June 27, 2013, Accepted July 8, 2013
Convenient synthetic method for 4-arylethylpyrazoles and 4-styrylpyrazoles was developed using α-alkenyl-
α,β-enones readily accessed from the Morita-Baylis-Hillman reaction. For the synthesis of 4-arylethyl-
pyrazole, the reactions with arylhydrazines needed to be carried out in o-dichlorobenzene under N2 balloon
atmosphere. On the other hand, 4-styrylpyrazoles required the reactions in ethanol under O2 balloon atmosphere.
Key Words : Pyrazoles, α-Alkenyl-α,β-enones, Morita-Baylis-Hillman adducts, 1,3-H shift, Aerobic oxidation
Introduction
pyrazole by a rapid 1,3-H shift. During our recent studies
8
using α-styryl-α,β-enones, which was prepared from MBH
1,3,4,5-Tetrasubstituted pyrazole derivatives are important
synthetic targets due to their wide spectrum of biological
bromide, we envisioned that the reaction of enone 1a and
phenylhydrazine could provide 4-styrylpyrazoline I and
eventually 4-phenethylpyrazole 3a via a double 1,3-H shift
1-5
activities. Therefore, numerous methods have been report-
2-5
ed for the synthesis of tetrasubstituted pyrazoles. The
9
process (Scheme 1).
condensation reaction between 1,3-dicarbonyl compounds
and substituted hydrazines is the simplest synthetic method
The starting material 1a was prepared from MBH adduct
of methyl vinyl ketone via a simple two-step procedure,
according to the reported method, namely a bromination and
2
for pyrazoles. The reaction of β-hydroxyketones or α,β-
8
a Wittig reaction with benzaldehyde. At the outset of our
enones with substituted hydrazines provided pyrazolines,
which could be oxidized to the corresponding pyrazoles in
experiment, the reaction of 1a and phenylhydrazine hydro-
chloride (2a) was carried out in refluxing ClCH2CH2Cl for
30 h. 4-Phenethylpyrazole 3a was obtained as expected;
however, the yield of 3a was low (28%). The reaction with
phenylhydrazine or addition of an acid catalyst did not
3
the presence of an oxidant such as MnO2 or DDQ. Besides
these methods, numerous other synthetic approaches have
4,5
been reported.
o
improve the yield of 3a. The reaction in DMSO (80-90 C)
Results and Discussion
showed the formation of many intractable side products with
The Morita-Baylis-Hillman (MBH) adducts have been
low yield of 3a. Thus we examined the reaction at higher
6
o
temperature (130 C) in o-dichlorobenzene (ODCB). To our
used for the synthesis of various heterocyclic compounds,
7
including pyrazoles. In 2003, the first synthesis of poly-
delight, the yield of 3a increased to 51% in short time (2 h).
In the reaction, a trace amount of 4-styrylpyrazole 4a (2%,
vide infra) was also formed although the reaction was
performed under N2 balloon atmosphere. Compound 4a
must be formed via an aerobic oxidation of the intermediate
substituted pyrazoles from MBH adducts has been reported
7a
in our group, as shown in Scheme 1. The reaction of MBH
adduct and substituted hydrazine provided 4-methylene-
pyrazoline intermediate which was converted to 4-methyl-
Scheme 1

2916 Bull. Korean Chem. Soc. 2013, Vol. 34, No. 10
Sung Hwan Kim et al.
a
Table 1. Synthesis of 4-arylethylpyrazoles
was obtained unexpectedly in moderate yield (54%) instead
of the corresponding pyrazole 3g, as shown in Scheme 2.
The mechanism of the formation of pyridazine 5a could be
proposed as follows. The cyclization of hydrazone inter-
11
mediate III might occur in a 6-endo mode, presumably
because of the electron-withdrawing nitro group. Subsequent
proton-transfer processes produced a pyridazine 5a.
As described above, 4-styrylpyrazole 4a was isolated in
trace amount (2%) during the synthesis of 4-phenethyl-
pyrazole 3a in ODCB under N2 balloon atmosphere. The
yield of 4a increased to 29% in ODCB under O2 balloon
atmosphere (vide supra). In order to prepare 4a as a major
product, we examined the reaction of 1a and 2a in ethanol
under O2 balloon atmosphere. As shown in Scheme 3 the
yield of 4a increased to 45%, and trace amount of 3a (2%)
was obtained along with pyridazine 5b (7%). Increased yield
of 4a might be attributed to higher concentration of O2 in
EtOH solution than in ODCB. Compound 4a could be
converted to 3a quantitatively (98%) under the usual cata-
lytic hydrogenation conditions (Pd/C, EtOH, rt, H2 balloon,
4 h).
Product
4
R NHNH2HCl (2)
Entry1,3-Diene (1)
(%)
1
1a (R =Ph, R =Ph, R =Me)
2
3
4
2a (R =Ph)
1
2
3
4
5
6
3a (51)
3b (57)
3c (45)
3d (61)
3e (48)
3f (49)
4
2b (R =p-ClPh)
1a
1a
4
2c (R =PhCH2)
1
1b (R =Ph, R =Ph, R =Et)
2
3
2a
1
1c (R =p-ClPh, R =Ph, R =Me) 2a
2
3
1
1d (R =Ph, R =p-PhPh, R =Me) 2a
2
3
a
o
Conditions: 1 (0.5 mmol), 2 (1.2 equiv), ODCB, 130 C, N2 balloon, 2 h.
I or 3a, by a trace amount of oxygen in the reaction mix-
10
ture. Actually, when we carried out the reaction under O2
balloon atmosphere in ODCB, 4a was obtained in an
increased yield (29%) along with 3a (17%).
Based on the successful result we synthesized 4-styryl-
pyrazole derivatives 4b-e, as summarized in Table 2. The 4-
styrylpyrazoles 4b-e were isolated in moderate yields (37-
51%). Trace amounts of the corresponding 4-arylethyl-
pyrazoles and pyridazine derivatives were observed at the
right positions on TLC; however, these compounds were not
separated.
Encouraged by the promising results we carried out the
synthesis of 4-arylethylpyrazoles 3b-f, and the results are
summarized in Table 1. The reactions of 1a with p-chloro-
phenylhydrazine hydrochloride (2b) or benzylhydrazine
hydrochloride (2c) afforded the corresponding pyrazoles 3b
and 3c in moderate yields (entries 2 and 3). The reactions of
1b-d with 2a (entries 4-6) gave 3d-f in moderate yields (48-
61%).
As a next entry, an alkenyl derivative 1h was prepared and
the reaction with 2a was examined, as shown in Scheme 4.
Compound 1h was prepared from MBH acetate and 2-
nitropropane via the sequential addition-elimination and
However, when we carried out the reaction of 1,3-diene
1e, bearing a p-nitrophenyl moiety, pyridazine derivative 5a
Scheme 2
Scheme 3

Regioselective Synthesis of 1,3,4,5-Tetrasubstituted Pyrazoles
Bull. Korean Chem. Soc. 2013, Vol. 34, No. 10 2917
Scheme 4
a
+
271 (M +Na).
Table 2. Synthesis of 4-styrylpyrazoles
o
Compound 1b: 74%; Pale yellow solid, mp 51-52 C; IR
−1
1
(KBr) 1682, 1597, 1493, 1446 cm ; H NMR (CDCl3, 300
MHz) δ 1.13 (t, J = 7.2 Hz, 3H), 2.79 (q, J = 7.2 Hz, 2H),
6.89 (d, J = 16.5 Hz, 1H), 6.96 (dd, J = 16.5, 0.6 Hz, 1H),
13
7.15 (s, 1H), 7.16-7.40 (m, 10H); C NMR (CDCl3, 75
MHz) δ 8.6, 33.8, 122.1, 126.6, 128.0, 128.5, 128.6 (2C),
130.2, 134.9, 135.6, 135.8, 137.2, 138.8, 204.4; ESIMS m/z
Product
(%)
4
R NHNH2HCl (2)
Entry 1,3-Diene (1)
+
285 (M +Na).
1
2
3
1a
1a
1a
2a
4a (45)
4b (41)
o
Compound 1c: 78%; Pale yellow solid, mp 52-53 C; IR
4
2d (R =p-MeOPh)
−1 1
(KBr) 1680, 1585, 1490, 1445 cm ; H NMR (CDCl3, 300
4
2e (R =p-NH2SO2Ph) 4c (37)
MHz) δ 2.43 (s, 3H), 6.83 (dd, J = 16.5, 1.2 Hz, 1H), 6.97 (d,
1 2
1f (R =p-MeOPh, R =Ph,
13
J = 16.5 Hz, 1H), 7.16-7.38 (m, 10H); C NMR (CDCl3, 75
4
2a
4d (50)
3
R =Me)
1 2
1g (R =Ph, R =p-MeOPh,
MHz) δ 28.3, 122.2, 127.8, 128.6, 128.8, 129.0, 130.2,
133.6, 134.1, 135.3, 135.8, 138.1, 138.4, 200.6; ESIMS m/z
5
2b
4e (51)
3
R =Me)
+ +
305 (M +Na), 307 (M +Na+2).
a
Conditions: 1 (0.5 mmol), 2 (1.2 equiv), EtOH, reflux, O2 balloon, 3 h.
o
Compound 1d: 78%; Pale yellow solid, mp 98-99 C; IR
−1
1
(KBr) 1677, 1596, 1486, 1445 cm ; H NMR (CDCl3, 300
MHz) δ 2.45 (s, 3H), 6.93 (dd, J = 16.5, 1.2 Hz, 1H), 7.03 (d,
J = 16.5 Hz, 1H), 7.22-7.41 (m, 11H), 7.46-7.52 (m, 4H);
DBU-mediated elimination of nitrous acid. The reaction of
1h and 2a in EtOH (O2 balloon) afforded 4-isobutenyl-
pyrazole 6 in good yield (71%) while the reaction in ODCB
(N2 balloon) produced 4-isobutenylpyrazoline 7 as a major
product (70%). It is interesting to note that the formation of
4-isobutylpyrazole 8 was not observed, as for the conversion
of I to 3a (vide supra, Scheme 1).
13
C NMR (CDCl3, 75 MHz) δ 28.4, 121.8, 126.9, 127.1,
127.3, 127.4, 128.5, 128.8, 128.9, 130.3, 134.9, 135.5,
136.3, 137.7, 138.5, 140.5, 140.7, 200.9; ESIMS m/z 347
+
(M +Na).
o
Compound 1e: 65%; Pale yellow solid, mp 108-109 C;
−1
1
In summary, we disclosed convenient syntheses of both 4-
arylethylpyrazoles (ODCB, N2 balloon) and 4-styrylpyra-
zoles (EtOH, O2 balloon) by the reactions of arylhydrazines
and α-alkenyl-α,β-enones, which were prepared from Morita-
Baylis-Hillman adducts.
IR (KBr) 1682, 1591, 1516, 1344 cm ; H NMR (CDCl3,
300 MHz) δ 2.47 (s, 3H), 6.83 (dd, J = 16.5, 1.2 Hz, 1H),
6.96 (d, J = 16.5 Hz, 1H), 7.15 (s, 1H), 7.20-7.34 (m, 5H),
13
7.54 (d, J = 8.7 Hz, 2H), 8.18 (d, J = 8.7 Hz, 2H); C NMR
(CDCl3, 75 MHz) δ 28.6, 120.5, 123.7, 126.8, 128.7, 128.8,
130.7, 133.3, 136.5, 137.3, 141.8, 142.1, 147.3, 200.7;
+
ESIMS m/z 316 (M +Na).
Experimental Section
o
Compound 1f: 80%; Pale yellow solid, mp 77-78 C; IR
−1
1
Preparation of Starting Materials 1a-h. The starting
materials 1a-g were prepared according to the reported
(KBr) 1672, 1603, 1508, 1256 cm ; H NMR (CDCl3, 300
MHz) δ 2.50 (s, 3H), 3.84 (s, 3H), 6.91 (d, J = 9.0 Hz, 2H),
6.96 (dd, J = 16.8, 1.2 Hz, 1H), 7.06 (d, J = 16.8 Hz, 1H),
8
method, and the spectroscopic data of 1a-h are as follows.
13
7.23-7.36 (m, 5H), 7.40-7.48 (m, 3H); C NMR (CDCl3, 75
Compound 1a: 81%; Pale yellow oil; IR (film) 1680,
−1 1
1588, 1566, 1493, 1445 cm ; H NMR (CDCl3, 300 MHz) δ
MHz) δ 28.2, 55.3, 114.0, 122.3, 126.5, 127.8, 128.0, 128.6,
132.1, 135.0, 136.5, 137.4, 138.2, 160.2, 200.5; ESIMS m/z
2.44 (s, 3H), 6.89 (dd, J = 16.5, 0.9 Hz, 1H), 6.98 (d, J =
13
16.5 Hz, 1H), 7.13-7.40 (m, 11H); C NMR (CDCl3, 75
+
301 (M +Na).
MHz) δ 28.3, 121.7, 126.6, 128.0, 128.5, 128.6, 128.8,
130.2, 135.3, 135.4, 137.2, 137.7, 138.5, 200.8; ESIMS m/z
Compound 1g: 61%; Pale yellow oil; IR (film) 1699,
−1 1
1605, 1510, 1250 cm ; H NMR (CDCl3, 300 MHz) δ 2.51

2918 Bull. Korean Chem. Soc. 2013, Vol. 34, No. 10
Sung Hwan Kim et al.
(s, 3H), 3.80 (s, 3H), 6.85 (dd, J = 16.5, 0.9 Hz, 1H), 6.86 (d,
J = 9.0 Hz, 2H), 7.00 (d, J = 16.5 Hz, 1H), 7.25 (s, 1H),
128.3, 128.5, 128.66, 128.71, 129.3, 131.0, 134.1, 139.4,
+ +
139.8, 141.3, 148.5; ESIMS m/z 373 (M +H), 375 (M +H+2).
13
7.32-7.48 (m, 7H); C NMR (CDCl3, 75 MHz) δ 28.4, 55.3,
Compound 3f: 49%; Pale yellow oil; IR (film) 1599,
−1
1
114.1, 119.7, 127.9, 128.4, 128.6, 130.0, 130.2, 134.8, 135.6,
1504, 1485, 1364 cm ; H NMR (CDCl3, 300 MHz) δ 2.35
(s, 3H), 2.74-2.81 (m, 4H), 7.02-7.05 (m, 2H), 7.11 (d, J =
8.1 Hz, 2H), 7.15-7.34 (m, 9H), 7.40 (d, J = 7.8 Hz, 2H),
+
136.6, 138.9, 159.6, 201.2; ESIMS m/z 301 (M +Na).
Compound 1h: 54%; Pale yellow oil; IR (film) 1676,
−1
1
13
7.45 (d, J = 8.1 Hz, 2H), 7.55 (d, J = 7.8 Hz, 2H); C NMR
1591, 1491, 1447, 1352 cm ; H NMR (CDCl3, 300 MHz) δ
1.42 (d, J = 0.9 Hz, 3H), 1.88 (d, J = 1.2 Hz, 3H), 2.36 (s,
3H), 5.97-6.00 (m, 1H), 7.29-7.37 (m, 4H), 7.54-7.57 (m,
(CDCl3, 75 MHz) δ 12.1, 25.6, 36.4, 118.6, 124.4, 126.3,
126.93, 126.96, 127.0, 128.0, 128.4, 128.6, 128.7, 128.9,
129.7, 130.9, 138.9, 140.1, 140.6, 140.7, 141.0, 148.4;
13
2H); C NMR (CDCl3, 75 MHz) δ 19.8, 25.5, 27.6, 119.9,
+
ESIMS m/z 415 (M +H). Anal. Calcd for C30H26N2: C,
128.3, 128.9, 130.3, 135.7, 137.6, 137.8, 138.8, 200.7;
+
ESIMS m/z 223 (M +Na).
86.92; H, 6.32; N, 6.76. Found: C, 86.68; H, 6.54; N, 6.68.
o
Compound 5a: 54%; Pale yellow solid, mp 136-138 C;
Typical Procedure for the Synthesis of 3a. A stirred
mixture of 1a (124 mg, 0.5 mmol) and 2a (87 mg, 0.6 mmol)
−1
1
IR (KBr) 3352, 1603, 1516, 1497, 1344 cm ; H NMR
(CDCl3, 300 MHz) δ 1.98 (s, 3H), 3.83 (s, 2H), 6.04 (s, 1H),
6.37-6.40 (m, 3H), 6.76-6.82 (m, 1H), 7.05-7.18 (m, 5H),
o
in ODCB (1.5 mL) was heated to 130 C for 2 h under N2
balloon atmosphere. After the usual extractive workup and
column chromatographic purification process (hexanes/Et2O,
20:1), compound 3a was isolated as colorless oil (87 mg,
51%) along with 4a as a white solid (4 mg, 2%). Other 4-
arylethylpyrazoles 3b-f were synthesized similarly, and the
spectroscopic data of 3a-f and 5a are as follows.
13
7.28-7.34 (m, 4H), 8.06 (d, J = 9.0 Hz, 2H); C NMR
(CDCl3, 75 MHz) δ 9.3, 32.7, 107.0, 112.2, 115.8, 120.7,
123.6, 126.5, 127.3, 127.9, 128.3, 129.1, 129.5, 131.8,
+
132.9, 146.2, 147.6, 149.9; ESIMS m/z 384 (M +H). Anal.
Calcd for C24H21N3O2: C, 75.18; H, 5.52; N, 10.96. Found:
C, 75.43; H, 5.47; N, 10.78.
Compound 3a: 51%; Colorless oil; IR (film) 1599, 1504,
−1 1
1452, 1364 cm ; H NMR (CDCl3, 300 MHz) δ 2.24 (s,
Typical Procedure for the Synthesis of 4a. A stirred
mixture of 1a (124 mg, 0.5 mmol) and 2a (87 mg, 0.6 mmol)
in EtOH (1.5 mL) was heated to reflux for 3 h under O2
balloon atmosphere. After the usual extractive workup and
column chromatographic purification process (hexanes/
Et2O, 20:1), compound 4a was isolated as a white solid (76
mg, 45%) along with 3a (4 mg, 2%) and 5b (12 mg, 7%).
Other 4-styrylpyrazoles 4b-e were synthesized similarly, and
the spectroscopic data of 4a-e, 5b, 6 and 7 are as follows.
3H), 2.62-2.69 (m, 4H), 6.95-7.00 (m, 4H), 7.05-7.24 (m,
13
11H); C NMR (CDCl3, 75 MHz) δ 12.1, 25.7, 36.9, 118.7,
124.4, 125.9, 126.3, 128.0, 128.3, 128.4, 128.5, 128.6,
129.7, 130.9, 140.1, 140.7, 141.6, 148.4; ESIMS m/z 339
+
(M +H). Anal. Calcd for C24H22N2: C, 85.17; H, 6.55; N,
8.28. Found: C, 85.32; H, 6.79; N, 8.13.
Compound 3b: 57%; Pale yellow oil; IR (film) 1595,
−1 1
1495, 1452, 1364 cm ; H NMR (CDCl3, 300 MHz) δ 2.22
o
Compound 4a: 45%; White solid, mp 127-128 C; IR
(s, 3H), 2.60-2.68 (m, 4H), 6.92-6.98 (m, 4H), 7.03 (d, J =
13
C
−1 1
(KBr) 1597, 1504, 1427, 1379 cm ; H NMR (CDCl3, 300
9.0 Hz, 2H), 7.08-7.18 (m, 5H), 7.21-7.26 (m, 3H);
NMR (CDCl3, 75 MHz) δ 12.1, 25.6, 36.8, 119.1, 125.3,
MHz) δ 2.53 (s, 3H), 6.71 (d, J = 16.5 Hz, 1H), 6.83 (d, J =
13
126.0, 128.3 (2C), 128.5, 128.6, 128.7, 129.7, 130.6, 131.8,
16.5 Hz, 1H), 7.09-7.25 (m, 10H), 7.27-7.31 (m, 5H);
C
+
138.6, 140.7, 141.4, 148.8; ESIMS m/z 373 (M +H), 375
NMR (CDCl3, 75 MHz) δ 14.4, 117.5, 119.8, 124.7, 125.9,
+
(M +H+2). Anal. Calcd for C24H21ClN2: C, 77.30; H, 5.68;
126.9, 127.0, 128.3, 128.5, 128.55, 128.57, 128.7, 130.1,
+
130.3, 138.1, 139.7, 141.2, 147.6; ESIMS m/z 337 (M +H).
N, 7.51. Found: C, 77.37; H, 5.81; N, 7.36.
Compound 3c: 45%; Pale yellow oil; IR (film) 1603,
Anal. Calcd for C24H20N2: C, 85.68; H, 5.99; N, 8.33. Found:
C, 85.59; H, 6.17; N, 8.19.
−1 1
1495, 1452, 1377 cm ; H NMR (CDCl3, 300 MHz) δ 2.16
o
Compound 4b: 41%; Pale yellow solid, mp 130-131 C;
(s, 3H), 2.51-2.64 (m, 4H), 5.03 (s, 2H), 6.83-6.92 (m, 6H),
13
7.07-7.27 (m, 9H); C NMR (CDCl3, 75 MHz) δ 12.1, 25.6,
−1
1
IR (KBr) 1638, 1516, 1462, 1447, 1248 cm ; H NMR
(CDCl3, 300 MHz) δ 2.59 (s, 3H), 3.77 (s, 3H), 6.76 (d, J =
16.5 Hz, 1H), 6.78 (d, J = 9.0 Hz, 2H), 6.90 (d, J = 16.5 Hz,
36.8, 52.7, 116.9, 125.8, 126.7, 127.2, 128.2, 128.3, 128.38,
128.40, 128.6, 129.8, 130.6, 138.1, 141.6, 142.1, 146.9;
+
ESIMS m/z 353 (M +H).
13
1H), 7.13 (d, J = 9.0 Hz, 2H), 7.18-7.38 (m, 10H); C NMR
Compound 3d: 61%; Colorless oil; IR (film) 1597, 1504,
(CDCl3, 75 MHz) δ 14.4, 55.4, 113.9, 117.0, 119.9, 125.9,
−1
1
1452, 1443, 1371 cm ; H NMR (CDCl3, 300 MHz) δ 1.37
(t, J = 7.8 Hz, 3H), 2.72 (q, J = 7.8 Hz, 2H), 2.73 (app s, 4H),
7.03-7.08 (m, 4H), 7.12-7.25 (m, 8H), 7.27-7.31 (m, 3H);
126.2, 126.9, 128.1, 128.4, 128.52, 128.54, 130.2, 130.3,
+
133.0, 138.2, 141.2, 147.2, 158.4; ESIMS m/z 367 (M +H).
o
Compound 4c: 37%; Pale yellow solid, mp 243-244 C;
13
−1
1
C NMR (CDCl3, 75 MHz) δ 13.8, 20.1, 25.6, 37.2, 118.1,
IR (KBr) 3424, 1647, 1595, 1333, 1161 cm ; H NMR
(CDCl3+DMSO-d6, 300 MHz) δ 2.58 (s, 3H), 6.73 (br s,
2H), 6.76 (d, J = 16.5 Hz, 1H), 6.85 (d, J = 16.5 Hz, 1H),
7.17-7.22 (m, 1H), 7.24-7.36 (m, 8H), 7.42-7.45 (m, 3H),
124.4, 125.9, 126.2, 128.0, 128.2, 128.4 (2C), 128.5, 129.7,
+
131.1, 140.1, 140.5, 141.6, 153.5; ESIMS m/z 353 (M +H).
Compound 3e: 48%; Pale yellow oil; IR (film) 1597,
−1 1
1504, 1493, 1452, 1364 cm ; H NMR (CDCl3, 300 MHz) δ
13
7.80 (d, J = 9.0 Hz, 2H); C NMR (CDCl3+DMSO-d6, 75
2.24 (s, 3H), 2.58-2.71 (m, 4H), 6.80 (d, J = 8.4 Hz, 2H),
MHz) δ 13.9, 118.0, 118.6, 123.3, 125.3, 126.3, 126.6,
13
6.94-6.97 (m, 2H), 7.05-7.19 (m, 10H); C NMR (CDCl3,
128.0, 128.3, 128.4, 128.5, 129.2, 129.6, 137.2, 140.6,
+
140.8, 141.6, 147.91; ESIMS m/z 416 (M +H).
75 MHz) δ 12.1, 25.6, 36.7, 118.8, 124.4, 126.0, 126.6,

Regioselective Synthesis of 1,3,4,5-Tetrasubstituted Pyrazoles
Bull. Korean Chem. Soc. 2013, Vol. 34, No. 10 2919
o
Compound 4d: 50%; Pale yellow solid, mp 125-126 C;
Huang, Y. R.; Katzenellenbogen, J. A. Org. Lett. 2000, 2, 2833-
2836. (c) Lamberth, C. Heterocycles 2007, 71, 1467-1502.
2. For some selected articles on the synthesis of pyrazoles from β-
diketones, see: (a) Jiang, J.-A.; Du, C.-Y.; Gu, C.-H.; Ji, Y.-F.
Synlett 2012, 23, 2965-2968. (b) Polshettiwar, V.; Varma, R. S.
Tetrahedron Lett. 2008, 49, 397-400. (c) Polshettiwar, V.; Varma,
R. S. Tetrahedron 2010, 66, 1091-1097. (d) Devery, J. J., III;
Mohanta, P. K.; Casey, B. M.; Flowers, R. A., II Synlett 2009,
1490-1494. (e) Wang, Z.-X.; Qin, H.-L. Green Chem. 2004, 6, 90-
92.
−1
1
IR (KBr) 1597, 1512, 1501, 1431, 1250 cm ; H NMR
(CDCl3, 300 MHz) δ 2.59 (s, 3H), 3.82 (s, 3H), 6.78 (d, J =
16.5 Hz, 1H), 6.89 (d, J = 9.0 Hz, 2H), 6.90 (d, J = 16.5 Hz,
13
1H), 7.13-7.38 (m, 12H); C NMR (CDCl3, 75 MHz) δ
14.5, 55.2, 114.0, 117.3, 120.0, 122.3, 124.7, 125.9, 126.8,
126.9, 128.0, 128.6, 128.7, 131.5, 138.2, 139.8, 141.1,
+
147.6, 159.6; ESIMS m/z 367 (M +H).
o
Compound 4e: 51%; Pale yellow solid, mp 135-136 C;
3. For the synthesis of pyrazoles from α,β-unsaturated ketones, see:
(a) Katrizky, A. R.; Wang, M.; Zhang, S.; Voronkov, M.; Steel, P.
J. J. Org. Chem. 2001, 66, 6787-6791. (b) Landge, S. M.; Schmidt,
A.; Outerbridge, V.; Torok, B. Synlett 2007, 1600-1604. (c) Pinto,
D. C. G. A.; Silva, A. M. S.; Levai, A.; Cavaleiro, J. A. S.;
Patonay, T.; Elguero, J. Eur. J. Org. Chem. 2000, 2593-2599. (d)
Zhou, H.-B.; Carlson, K. E.; Stossi, F.; Katzenellenbogen, B. S.;
Katzenellenbogen, J. A. Bioorg. Med. Chem. Lett. 2009, 19, 108-
110.
−1
1
IR (KBr) 1605, 1506, 1464, 1248 cm ; H NMR (CDCl3,
300 MHz) δ 2.57 (s, 3H), 3.80 (s, 3H), 6.73 (app s, 2H), 6.84
(d, J = 9.0 Hz, 2H), 7.14 (d, J = 9.0 Hz, 2H), 7.20-7.25 (m,
13
4H), 7.29 (d, J = 9.0 Hz, 2H), 7.36-7.41 (m, 3H); C NMR
(CDCl3, 75 MHz) δ 14.4, 55.3, 114.0, 117.4, 118.1, 125.6,
127.1, 128.2, 128.6, 128.73, 128.9, 130.0, 130.2, 130.8,
+
132.3, 138.3, 140.8, 147.9, 158.9; ESIMS m/z 401 (M +H),
+
403 (M +H+2). Anal. Calcd for C25H21ClN2O: C, 74.90; H,
4. For the synthesis of pyrazoles from ethynyl ketones or their
derivatives, see: (a) Bagley, M. C.; Lubinu, M. C.; Mason, C.
Synlett 2007, 704-708. (b) Dadiboyena, S.; Valente, E. J.; Hamme
II, A. T. Tetrahedron Lett. 2010, 51, 1341-1343. (c) Hao, L.;
Hong, J.-J.; Zhu, J.; Zhan, Z.-P. Chem. Eur. J. 2013, 19, 5715-
5720.
5.28; N, 6.99. Found: C, 75.07; H, 5.44; N, 6.78.
Compound 5b: 7%; Pale yellow oil; IR (film) 3350,
−1
1
1601, 1495, 1452 cm ; H NMR (CDCl3, 300 MHz) δ 2.07
(s, 3H), 3.83 (s, 2H), 6.16 (s, 1H), 6.44 (s, 1H), 6.48 (d, J =
7.8 Hz, 2H), 6.83-6.89 (m, 1H), 7.11-7.32 (m, 10H), 7.40 (d,
5. For the other synthesis of pyrazoles, see: (a) Guo, S.; Wang, J.;
Guo, D.; Zhang, X.; Fan, X. RSC Adv. 2012, 2, 3772-3777. (b)
Guo, S.; Wang, J.; Guo, D.; Zhang, X.; Fan, X. Tetrahedron 2012,
68, 7768-7774. (c) Browne, D. L.; Taylor, J. B.; Plant, A.; Harrity,
J. P. A. J. Org. Chem. 2009, 74, 396-400. (d) Browne, D. L.; Vivat,
J. F.; Plant, A.; Gomez-Bengoa, E.; Harrity, J. P. A. J. Am. Chem.
Soc. 2009, 131, 7762-7769. (e) Kinjo, R.; Donnadieu, B.; Bertrand,
G. Angew. Chem. Int. Ed. 2011, 50, 5560-5563. (f) Deng, X.;
Mani, N. S. Org. Lett. 2008, 10, 1307-1310. (g) Deng, X.; Mani,
N. S. Org. Lett. 2006, 8, 3505-3508. (h) Deng, X.; Mani, N. S. J.
Org. Chem. 2008, 73, 2412-2415. (i) Panda, N.; Jena, A. K. J.
Org. Chem. 2012, 77, 9401-9406.
13
J = 6.9 Hz, 2H); C NMR (CDCl3, 75 MHz) δ 9.4, 32.7,
107.4, 112.3, 117.6, 120.6, 125.7, 126.2, 127.3, 127.6, 128.2,
128.3, 128.4, 129.4, 132.1, 132.4, 141.9, 147.8; ESIMS m/z
+
339 (M +H).
Compound 6: 71%; Pale yellow oil; IR (film) 1599,
−1
1
1504, 1445, 1375, 1364 cm ; H NMR (CDCl3, 300 MHz) δ
1.46 (d, J = 1.2 Hz, 3H), 1.82 (d, J = 1.2 Hz, 3H), 2.27 (s,
3H), 5.86-5.89 (m, 1H), 7.13-7.17 (m, 2H), 7.20-7.30 (m,
13
8H); C NMR (CDCl3, 75 MHz) δ 12.7, 20.0, 25.5, 114.9,
6. For the general reviews on MBH reaction, see: (a) Basavaiah, D.;
Rao, A. J.; Satyanarayana, T. Chem. Rev. 2003, 103, 811-891. (b)
Basavaiah, D.; Reddy, B. S.; Badsara, S. S. Chem. Rev. 2010, 110,
5447-5674. (c) Singh, V.; Batra, S. Tetrahedron 2008, 64, 4511-
4574. (d) Declerck, V.; Martinez, J.; Lamaty, F. Chem. Rev. 2009,
109, 1-48. (e) Ciganek, E. In Organic Reactions; Paquette, L. A.,
Ed.; John Wiley & Sons: New York, 1997; Vol. 51, pp 201-350.
(f) Kim, J. N.; Lee, K. Y. Curr. Org. Chem. 2002, 6, 627-645. (g)
Lee, K. Y.; Gowrisankar, S.; Kim, J. N. Bull. Korean Chem. Soc.
2005, 26, 1481-1490. (h) Gowrisankar, S.; Lee, H. S.; Kim, S. H.;
Lee, K. Y.; Kim, J. N. Tetrahedron 2009, 65, 8769-8780. (i) Shi,
M.; Wang, F.-J.; Zhao, M.-X.; Wei, Y. The Chemistry of the Morita-
Baylis-Hillman Reaction; RSC Publishing: Cambridge, UK, 2011.
7. For the synthesis of pyrazoles from MBH adducts, see: (a) Lee, K.
Y.; Kim, J. M.; Kim, J. N. Tetrahedron Lett. 2003, 44, 6737-6740.
(b) Kim, H. S.; Kim, S. H.; Kim, J. N. Bull. Korean Chem. Soc.
2007, 28, 1841-1843. (c) Mamaghani, M.; Dastmard, S. ARKIVOC
2009 (ii), 168-173. (d) Nikpassand, M.; Mamaghani, M.;
Tabatabaeian, K.; Abiazi, M. K. Mol. Divers. 2009, 13, 389-393.
8. For the synthesis of 1,3-dienes from MBH adducts and their
synthetic applications, see: (a) Lim, C. H.; Kim, S. H.; Park, K.
H.; Lee, J.; Kim, J. N. Tetrahedron Lett. 2013, 54, 387-391. (b)
Lee, C. G.; Lee, K. Y.; Kim, S. J.; Kim, J. N. Bull. Korean Chem.
Soc. 2007, 28, 719-720. (c) Zhou, R.; Wang, C.; Song, H.; He, Z.
Org. Lett. 2010, 12, 976-979. (d) Crist, R. M.; Reddy, P. V.;
Borhan, B. Tetrahedron Lett. 2001, 42, 619-621. (e) Muthiah, C.;
Senthil Kumar, K.; Vittal, J. J.; Kumara Swamy, K. C. Synlett
2002, 1787-1790. (f) Palmelund, A.; Myers, E. L.; Tai, L. R.;
Tisserand, S.; Butts, C. P.; Aggarwal, V. K. Chem. Commun. 2007,
4128-4130.
118.3, 124.9, 126.6, 127.7, 128.2, 128.7, 129.6, 131.1,
+
137.7, 140.0, 140.2, 148.6; ESIMS m/z 289 (M +H). Anal.
Calcd for C20H20N2: C, 83.30; H, 6.99; N, 9.71. Found: C,
83.21; H, 7.23; N, 9.65.
Compound 7: 70%; Pale yellow oil; IR (film) 1599,
−1
1
1499, 1452, 1341 cm ; H NMR (CDCl3, 300 MHz) δ 1.46
(d, J = 1.5 Hz, 3H), 1.78 (d, J = 1.5 Hz, 3H), 1.95 (d, J = 1.2
Hz, 3H), 3.68-3.75 (m, 1H), 4.56 (d, J = 9.0 Hz, 1H), 5.13-
5.19 (m, 1H), 6.72-6.77 (m, 1H), 6.93 (d, J = 7.8 Hz, 2H),
13
7.10-7.16 (m, 2H), 7.24-7.32 (m, 5H); C NMR (CDCl3, 75
MHz) δ 14.3, 18.2, 25.8, 60.0, 72.2, 113.5, 118.9, 121.7,
125.8, 127.3, 128.8, 128.9, 136.4, 142.2, 146.4, 151.2;
+
ESIMS m/z 291 (M +H).
Acknowledgments. This research was supported by Basic
Science Research Program through the National Research
Foundation of Korea (NRF) funded by the Ministry of
Education, Science and Technology (2012R1A1B3000541).
Spectroscopic data were obtained from the Korea Basic
Science Institute, Gwangju branch.
References and Notes
1. For the synthesis of fully-substituted pyrazoles and their appli-
cations, see: (a) Dadiboyena, S.; Nefzi, A. Eur. J. Med. Chem.
2011, 46, 5258-5275 and further references cited therein. (b)
9. For the synthesis of styryl- and/or phenethyl-substituted pyrazoles,

2920 Bull. Korean Chem. Soc. 2013, Vol. 34, No. 10
Sung Hwan Kim et al.
see: (a) Yamamoto, S.; Tomita, N.; Suzaki, Y.; Suzuki, T.; Kaku,
T.; Hara, T.; Yamaoka, M.; Kanzaki, N.; Hasuoka, A.; Baba, A.;
Ito, M. Bioorg. Med. Chem. 2012, 20, 2338-2352. (b) Silva, V. L.
M.; Silva, A. M. S.; Pinto, D. C. G. A.; Elguero, J.; Cavaleiro, J.
A. S. Eur. J. Org. Chem. 2009, 4468-4479. (c) Barawkar, D. A.;
Bandyopadhyay, A.; Deshpande, A.; Koul, S.; Kandalkar, S.;
Patil, P.; Khose, G.; Vyas, S.; Mone, M.; Bhosale, S.; Singh, U.;
De, S.; Meru, A.; Gundu, J.; Chugh, A.; Palle, V. P.; Mookhtiar, K.
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Med. Chem. Lett. 2012, 22, 4341-4347.
Alex, K.; Tillack, A.; Schwarz, N.; Beller, M. Org. Lett. 2008, 10,
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Plazzi, P. V.; Terstappen, G. C. Bioorg. Med. Chem. 2008, 16,
2043-2052.
11. For the synthesis of pyridazines from the hydrazones of β,γ-
enones via 6-endo cyclization, see: (a) Heinisch, G.; Holzer, W.;
Nawwar, G. A. M. J. Heterocyclic Chem. 1986, 23, 93-96. (b) Al-
Awadi, N. A.; Ibrahim, M. R.; Al-Etaibi, A. M.; Elnagdi, M. H.
ARKIVOC 2011 (ii) 310-321. (c) Abdelhamid, I. A.; Darwish, E.
S.; Nasra, M. A.; Abdel-Gallil, F. M.; Fleita, D. H. ARKIVOC
2008, (xvii) 117-121.
10. For the aerobic oxidation of pyrazolines to pyrazoles, see: (a)